HTLV-1 CTCF-binding site is dispensable for in vitro immortalization and persistent infection in vivo
Abstract Background Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma (ATL) and the neurological disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The exact mechanism(s) through which latency and disease progression are r...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2019-12-01
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| Series: | Retrovirology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12977-019-0507-9 |
| _version_ | 1828937822656004096 |
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| author | Michael P. Martinez Xiaogang Cheng Ancy Joseph Jacob Al-Saleem Amanda R. Panfil Marilly Palettas Wessel P. Dirksen Lee Ratner Patrick L. Green |
| author_facet | Michael P. Martinez Xiaogang Cheng Ancy Joseph Jacob Al-Saleem Amanda R. Panfil Marilly Palettas Wessel P. Dirksen Lee Ratner Patrick L. Green |
| author_sort | Michael P. Martinez |
| collection | DOAJ |
| description | Abstract Background Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma (ATL) and the neurological disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The exact mechanism(s) through which latency and disease progression are regulated are not fully understood. CCCTC-binding factor (CTCF) is an 11-zinc finger, sequence-specific, DNA-binding protein with thousands of binding sites throughout mammalian genomes. CTCF has been shown to play a role in organization of higher-order chromatin structure, gene expression, genomic imprinting, and serve as a barrier to epigenetic modification. A viral CTCF-binding site (vCTCF-BS) was previously identified within the overlapping p12 (sense) and Hbz (antisense) genes of the HTLV-1 genome. Thus, upon integration, HTLV-1 randomly inserts a vCTCF-BS into the host genome. vCTCF-BS studies to date have focused primarily on HTLV-1 chronically infected or tumor-derived cell lines. In these studies, HTLV-1 was shown to alter the structure and transcription of the surrounding host chromatin through the newly inserted vCTCF-BS. However, the effects of CTCF binding in the early stages of HTLV-1 infection remains unexplored. This study examines the effects of the vCTCF-BS on HTLV-1-induced in vitro immortalization and in vivo viral persistence in infected rabbits. Results HTLV-1 and HTLV-1∆CTCF LTR-transactivation, viral particle production, and immortalization capacity were comparable in vitro. The total lymphocyte count, proviral load, and Hbz gene expression were not significantly different between HTLV-1 and HTLV-1∆CTCF-infected rabbits throughout a 12 week study. However, HTLV-1∆CTCF-infected rabbits displayed a significantly decreased HTLV-1-specific antibody response compared to HTLV-1-infected rabbits. Conclusions Mutation of the HTLV-1 vCTCF-BS does not significantly alter T-lymphocyte transformation capacity or early in vivo virus persistence, but results in a decreased HTLV-1-specific antibody response during early infection in rabbits. Ultimately, understanding epigenetic regulation of HTLV-1 gene expression and pathogenesis could provide meaningful insights into mechanisms of immune evasion and novel therapeutic targets. |
| first_indexed | 2024-12-14T02:32:07Z |
| format | Article |
| id | doaj.art-5ea8196afd3b463a8743ece67d955677 |
| institution | Directory Open Access Journal |
| issn | 1742-4690 |
| language | English |
| last_indexed | 2024-12-14T02:32:07Z |
| publishDate | 2019-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Retrovirology |
| spelling | doaj.art-5ea8196afd3b463a8743ece67d9556772022-12-21T23:20:14ZengBMCRetrovirology1742-46902019-12-0116111310.1186/s12977-019-0507-9HTLV-1 CTCF-binding site is dispensable for in vitro immortalization and persistent infection in vivoMichael P. Martinez0Xiaogang Cheng1Ancy Joseph2Jacob Al-Saleem3Amanda R. Panfil4Marilly Palettas5Wessel P. Dirksen6Lee Ratner7Patrick L. Green8Center for Retrovirus Research, The Ohio State UniversityDivision of Oncology, Washington UniversityDivision of Oncology, Washington UniversityCenter for Retrovirus Research, The Ohio State UniversityCenter for Retrovirus Research, The Ohio State UniversityCenter for Biostatistics, The Ohio State UniversityCenter for Retrovirus Research, The Ohio State UniversityDivision of Oncology, Washington UniversityCenter for Retrovirus Research, The Ohio State UniversityAbstract Background Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma (ATL) and the neurological disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The exact mechanism(s) through which latency and disease progression are regulated are not fully understood. CCCTC-binding factor (CTCF) is an 11-zinc finger, sequence-specific, DNA-binding protein with thousands of binding sites throughout mammalian genomes. CTCF has been shown to play a role in organization of higher-order chromatin structure, gene expression, genomic imprinting, and serve as a barrier to epigenetic modification. A viral CTCF-binding site (vCTCF-BS) was previously identified within the overlapping p12 (sense) and Hbz (antisense) genes of the HTLV-1 genome. Thus, upon integration, HTLV-1 randomly inserts a vCTCF-BS into the host genome. vCTCF-BS studies to date have focused primarily on HTLV-1 chronically infected or tumor-derived cell lines. In these studies, HTLV-1 was shown to alter the structure and transcription of the surrounding host chromatin through the newly inserted vCTCF-BS. However, the effects of CTCF binding in the early stages of HTLV-1 infection remains unexplored. This study examines the effects of the vCTCF-BS on HTLV-1-induced in vitro immortalization and in vivo viral persistence in infected rabbits. Results HTLV-1 and HTLV-1∆CTCF LTR-transactivation, viral particle production, and immortalization capacity were comparable in vitro. The total lymphocyte count, proviral load, and Hbz gene expression were not significantly different between HTLV-1 and HTLV-1∆CTCF-infected rabbits throughout a 12 week study. However, HTLV-1∆CTCF-infected rabbits displayed a significantly decreased HTLV-1-specific antibody response compared to HTLV-1-infected rabbits. Conclusions Mutation of the HTLV-1 vCTCF-BS does not significantly alter T-lymphocyte transformation capacity or early in vivo virus persistence, but results in a decreased HTLV-1-specific antibody response during early infection in rabbits. Ultimately, understanding epigenetic regulation of HTLV-1 gene expression and pathogenesis could provide meaningful insights into mechanisms of immune evasion and novel therapeutic targets.https://doi.org/10.1186/s12977-019-0507-9HTLV-1CTCFRetrovirusImmortalizationPersistence |
| spellingShingle | Michael P. Martinez Xiaogang Cheng Ancy Joseph Jacob Al-Saleem Amanda R. Panfil Marilly Palettas Wessel P. Dirksen Lee Ratner Patrick L. Green HTLV-1 CTCF-binding site is dispensable for in vitro immortalization and persistent infection in vivo Retrovirology HTLV-1 CTCF Retrovirus Immortalization Persistence |
| title | HTLV-1 CTCF-binding site is dispensable for in vitro immortalization and persistent infection in vivo |
| title_full | HTLV-1 CTCF-binding site is dispensable for in vitro immortalization and persistent infection in vivo |
| title_fullStr | HTLV-1 CTCF-binding site is dispensable for in vitro immortalization and persistent infection in vivo |
| title_full_unstemmed | HTLV-1 CTCF-binding site is dispensable for in vitro immortalization and persistent infection in vivo |
| title_short | HTLV-1 CTCF-binding site is dispensable for in vitro immortalization and persistent infection in vivo |
| title_sort | htlv 1 ctcf binding site is dispensable for in vitro immortalization and persistent infection in vivo |
| topic | HTLV-1 CTCF Retrovirus Immortalization Persistence |
| url | https://doi.org/10.1186/s12977-019-0507-9 |
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